This study focuses on longitudinal clinical and biological evaluation for the treatment of mania, depression, and schizoaffective illness. In double-blind clinical trials, we have found evidence that the dopamine receptor active agents piribedil and pimozide possess clinical efficacy in depression and mania, respectively. The anticonvulsant carbamazepine is useful in the treatment of mania and may be of some prophylactic use in both manic and depressive phases, including in some lithium non-responders. A variety of neurotransmitter amines and their metabolites are measured in patients and controls. Preliminary data indicate that CSF norepinephrine is elevated, while its biosynthetic enzyme DBH is decreased in mania compared to controls. Approaches to neuroendocrine and polypeptide function in patients and volunteers are being pursued. A psychopharmacology laboratory is maintained for the study of animal models of psychopathology. Kindling and cocaine sensitization have proven most useful in the attempt to examine underlying mechanisms of behavioral pathology. The interaction of biological changes with psychological and cognitive alterations in the acute psychoses are considered in developing new research and treatment strategies for the affective psychoses.